Magnetic resonance imaging (MRI) produces exquisite renderings of human anatomy and pathology at high spatial resolution. To increase diagnostic sensitivity and specificity for MRI, such as with imaging for cancer, infection, neurological and cardiovascular diseases, contrast material is often administered intravenously before and/or during imaging to improve signal.
The most common MRI contrast material is based on molecular complexes containing the paramagnetic metal gadolinium (Gd). Gd is a heavy metal that is found in nature only in combined (salt) form. In water-soluble salts it is highly toxic, but chelated Gd has reduced toxicity. In the U.S., all nine MRI contrast agents approved by the Food and Drug Administration (FDA) are Gd-based. Gd possesses strong “paramagnetism” that results in a locally increased MRI signal on T1-weighted images. However, Gd-based contrast agents can cause a rare but severely debilitating condition called nephrogenic systemic fibrosis (NSF), a syndrome involving widespread fibrosis of the skin, joints, eyes, and internal organs. The World Health Organization and FDA have issued restrictions on the use of these Gd agents in patients with renal insufficiency/failure, with the FDA mandating a “black box” warning on all commercial contrast media containing Gd. As a consequence, millions of patients in the U.S., and many more worldwide, are no longer able to receive contrast material for MRI, severely limiting detection and characterization for several diseases. Additionally, in 2015 the FDA issued a drug safety communication indicating the agency is investigating the risk of brain deposits following repeated use of Gd-based contrast agents for MRI due to recent studies in people and animals demonstrating that Gd can remain in the brain, even in individuals with normal kidney function.
Other paramagnetic complexes, used more rarely either as investigational or as “off-label,” are usually based on large iron oxide-based nanoparticles developed and marketed as intravenous iron replacement therapy (e.g., FERAHEME® (ferumoxytol) injection). The use of these complexes for MRI is limited, however, by their large molecular size, which confines these agents to the subject's blood pool until they are finally cleared by the reticuloendothelial system (i.e., macrophages, liver, spleen).
U.S. Patent Application Publication 2014/0154185 to Van Zijl et al. discusses the use of parenteral glucose to enhance MRI. See also Yadav N N, Xu J, Bar-Shir A, Qin Q, Chan K W, Grgac K, Li W, McMahon M T, van Zijl P C, Natural D-glucose as a biodegradable MRI contrast agent for detecting cancer. Magn Reson Med. 2012 Dec.;68(6):1764-73; Yadav N N, Xu J, Bar-Shir A, Qin Q, Chan K W, Grgac K, Li W, McMahon M T, van Zijl P C, Natural D-glucose as a biodegradable MRI relaxation agent. Magn Reson Med. 2014 Sept.;72(3):823-28.
There remains a need for alternative/additional contrast agent compositions useful for MRI scanning technologies.